Entacapone (E-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide) is a catechol-O-methyl transferase (COMT) inhibitor often used in combination with levodopa and a dopa decarboxylase (DDC) inhibitor in the treatment of Parkinson's disease. Entacapone is commercially available in a stand-alone formulation under the trademarks Comtess® and Comtan®, and under trademark Stalevo® in a fixed combination (levodopa:carbidopa:entacapone: 50 mg:12.5 mg:200 mg, 100 mg:25 mg:200 mg and 150 mg:37.5 mg:200 mg).
U.S. Pat. No. 5,446,194 discloses a method for the preparation of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide by refluxing a solution containing 3,4-dihydroxy-5-nitrobenzaldehyde, N,N-diethyl-2-cyanoacetamide and a catalytic amount of piperidine acetate in dry ethanol. The yield of said method is 73%. The product is a crude mixture of the E and Z isomers of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide having a melting point of 153° C.-156° C. The condensation reaction used in U.S. Pat. No. 5,446,194 is called a Knoevenagel condensation.
U.S. Pat. No. 5,135,950 discloses a process for the preparation of a stable and crystallographically essentially pure polymorphic form A of E-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide having a melting point of 162° C.-163° C. Said process comprises crystallization of the above described crude mixture of the E and Z isomers of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide from a lower aliphatic carboxylic acid containing a catalytic amount of hydrochloric or hydrobromic acid. The yield of said crystallographically pure polymorphic form A is 70-80%.
WO 2005/070881 purports to disclose a process for manufacturing the stable polymorphic form A of E-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide without isolating a crude solid isomeric mixture of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide. In said method, the Knoevenagel condensation step is carried out in an alcohol such as methanol, ethanol, isopropanol, isobutanol, n-butanol, preferably isopropanol, at reflux temperature in the presence of a suitable organic base such as piperidine, N-methylmorpholine, pyridine, piperazine etc., preferably piperidine base. After the completion of the reaction, the mixture is poured into a mixture of chilled water and ethyl acetate. The pH of the solution is adjusted to between 3.5 and 4.0 by adding acid. The ethyl acetate layer is separated, washed with water and concentrated to obtain the (E)-isomer of polymorphic form A. A serious drawback of the method disclosed in WO 2005/070881 is that the total yield of the process is low, as the (Z)-isomer (about 30%) formed during the reaction is not recovered and remains in the reaction solution, thus interfering with the crystallization of the E-isomer.
WO 2005/063696 purports to disclose a method for producing N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide by heating 3,4-dihydroxy-5-nitrobenzaldehyde, raw N,N-diethyl-2-cyanoacetamide, acetic acid and diethyl amine in toluene, and by removing the water formed during the reaction through azeotropic distillation. A significant drawback of this method is that a large amount of solvent has to be used.